Maximum resection and immunotherapy improve glioblastoma patient survival: a retrospective single-institution prognostic analysis.

Glioblastoma (GBM) is a refractory disease with a poor prognosis and various methods, including maximum resection and immunotherapy, have been tested to improve outcomes. In this retrospective study we analyzed the prognostic factors of 277 newly diagnosed GBM patients over 11 years of consecutive cases at our institution to evaluate the effect of these methods on prognosis. Various data, including the extent of removal (EOR) and type of adjuvant therapy, were examined and prognostic relationships were analyzed. The median overall survival (OS) of the entire 277-case cohort, 200 non-biopsy cases, and 77 biopsy cases was 16.6 months, 19.7 months, and 9.7 months, respectively. Gross total removal (GTR; 100% of EOR) was achieved in 32.9% of the cases. Univariate analysis revealed younger age, right side, higher Karnofsky performance status, GTR, intraoperative magnetic resonance imaging (MRI) use for removal, proton therapy, combination immunotherapy, and discharge to home as good prognostic factors. Intraoperative MRI use and EOR were closely related. In the multivariate analysis, GTR, proton therapy, and a combination of immunotherapies, including autologous formalin-fixed tumor vaccine, were the significant prognostic factors. A multivariate analysis of 91 GTR cases showed that immunotherapy contributed to prognostic improvements. The median OS and 5-year OS % values were 36.9 months and 43.3% in GTR cases receiving immunotherapy. In conclusion, GTR, proton therapy, and immunotherapy were good prognostic factors in single-center GBM cases. Tumor vaccine therapy for GTR cases achieved a notably high median survival time and long-term survival ratio, indicating its usefulness in GTR cases.

Involvement of the optic pathway and outcome of visual function in patients with neurohypophyseal germ cell tumor.

BACKGROUND: Patients with neurohypophyseal germ cell tumors (GCTs) typically present with visual problems. Hence, this study aimed to assess optic pathway involvement based on clinical and radiological findings and to validate the outcome of visual function. METHODS: A total of 16 patients with newly diagnosed neurohypophyseal GCTs who were treated at the University of Tsukuba Hospital between 2000 and 2020 were included in this study. RESULTS: The median interval from symptom onset to diagnosis was 173.5 days (range, 33-1588 days). Patients with visual disturbance at diagnosis had a longer time to diagnosis compared with those without. Ophthalmologic abnormalities were frequently observed, with an incidence rate of 69%. Fifty percent of patients exhibited optic pathway involvement detected via magnetic resonance imaging (MRI). Visual impairment was more severe in the patients with optic pathway involvement (p = 0.002). Post-treatment visual impairment was improved but was still significantly severe in patients with optic pathway involvement than in those without involvement (p = 0.010). Visual field deficit more likely remained with an improvement rate of 50%, whereas the improvement rate of visual acuity was 78%. Further, none developed late-onset visual deterioration during the follow-up period. CONCLUSIONS: Visual disturbance and optic pathway involvement are common in neurohypophyseal GCTs. Visual impairment particularly in patients with optic pathway involvement on MRI is more likely to remain at follow-up, although the outcome of visual function is acceptable in most cases.

Novel Steroidal Glycosides from the Whole Plants of Helleborus foetidus.

Phytochemical analysis of the whole Helleborus foetidus plants identified 28 steroidal glycosides (1-28), including 20 novel spirostanol glycosides (1-20) and a novel furostanol glycoside (21). The structures of the newly identified compounds were elucidated by two-dimensional NMR spectroscopy and hydrolytic cleavage. Compounds 12, 13, and 15 were determined to be spirostanol trisdesmosides bearing sugar moieties at the C-1, -21, and -24 hydroxy groups of the aglycone unit. The isolated compounds were subsequently evaluated for cytotoxic activity against HL-60 human promyelocytic leukemia cells and A549 human lung carcinoma cells. In particular, 7 showed cytotoxic activity against the HL-60 and A549 cells, with IC50 values of 5.9 and 6.6 µM, respectively, whereas 19 was selectively cytotoxic to A549 cells with an IC50 value of 5.5 µM.

Genetic evidence implies that primary and relapsed tumors arise from common precursor cells in primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare subtype of lymphoma that arises within the brain or the eyes. PCNSL recurs within the central nervous system (CNS) in most relapsed cases, whereas extra-CNS relapse is experienced in rare cases. The present study aimed at identifying the presence of common precursor cells (CPC) for primary intra- and relapsed extra-CNS tumors, and further assessing the initiating events in bone marrow (BM). Targeted deep sequencing was carried out for five paired primary intra- and relapsed extra-CNS tumors of PCNSL. Two to five mutations were shared by each pair of intra- and extra-CNS tumors. In particular, MYD88 mutations, L265P in three and P258L in one, were shared by four pairs. Unique somatic mutations were observed in all five intra-CNS tumors and in four out of five extra-CNS tumors. Remarkably, IgH clones in the intra- and the extra-CNS tumors in two pairs were distinct from each other, whereas one pair of tumors shared identical monoclonal IgH rearrangement. In a cohort of 23 PCNSL patients, L265P MYD88 mutations were examined in tumor-free BM mononuclear cells (MNC) in which the PCNSL tumors had L265P MYD88 mutations. L265P MYD88 mutations were detected by a droplet digital PCR method in nine out of 23 bone marrow mononuclear cells. These results suggest that intra- and extra-tumors are derived from CPC with MYD88 mutations in most PCNSL, arising either before or after IgH rearrangement. The initiating MYD88 mutations may occur during B-cell differentiation in BM.

Pure germinoma occurring 11 years after total pineal mature teratoma removal: a case report and review of the literature.

Intracranial mature teratomas have good prognoses and are usually treated by total tumor resection. We report a rare case of a germinoma that occurred 11 years after total removal of a pineal mature teratoma. A 5-year-old boy presented with headache and nausea and was diagnosed with a pineal tumor and obstructive hydrocephalus on MRI. He underwent total removal of the lesion, which was pathologically diagnosed as a mature teratoma without any other germ cell tumor components. MR images after 11 years showed a newly developed pineal tumor, which was confirmed as a germinoma after neuroendoscopic biopsy. Chemoradiotherapy resulted in complete remission, without any symptoms. This case demonstrated possible late occurrence of germinoma even after total removal of a mature teratoma had been achieved. A long-term follow-up of 10 years or more should be planned for these patients.

Clinical significance of disease-specific MYD88 mutations in circulating DNA in primary central nervous system lymphoma.

Recent sequencing studies demonstrated the MYD88 L265P mutation in more than 70% of primary central nervous system lymphomas (PCNSL), and the clinical significance of this mutation has been proposed as diagnostic and prognostic markers in PCNSL. In contrast, mutational analyses using cell-free DNAs have been reported in a variety of systemic lymphomas. To investigate how sensitively the MYD88 L265P mutation can be identified in cell-free DNA from PCNSL patients, we carried out droplet digital PCR (ddPCR) and targeted deep sequencing (TDS) in 14 consecutive PCNSL patients from whom paired tumor-derived DNA and cell-free DNA was available at diagnosis. The MYD88 L265P mutation was found in tumor-derived DNA from all 14 patients (14/14, 100%). In contrast, among 14 cell-free DNAs evaluated by ddPCR (14/14) and TDS (13/14), the MYD88 L265P mutation was detected in eight out of 14 (ddPCR) and in 0 out of 13 (TDS) samples, implying dependence on the detection method. After chemotherapy, the MYD88 L265P mutation in cell-free DNAs was traced in five patients; unexpectedly, the mutations disappeared after chemotherapy was given, and they remained undetectable in all patients. These observations suggest that ddPCR can sensitively detect the MYD88 L265P mutation in cell-free DNA and could be used as non-invasive diagnostics, but may not be applicable for monitoring minimal residual diseases in PCNSL.

Long-term results of cabergoline therapy for macroprolactinomas and analyses of factors associated with remission after withdrawal.

OBJECTIVE: Withdrawal of cabergoline is generally challenging, especially in patients with large or invasive macroprolactinomas. Therefore, we aimed to assess long-term results of cabergoline therapy for macroprolactinomas and remission achievement results after withdrawal in patients with macroprolactinomas. We also investigated clinical characteristics and factors related to remission after withdrawal. METHODS: This was an institutional review board-approved retrospective analysis. We studied 46 macroprolactinoma patients who had taken cabergoline during the period from 2003 through 2013. Administration of cabergoline was maintained for 5 years before withdrawal. RESULTS: Median follow-up after the initiation of cabergoline therapy was 54·3 (range 5·3 to 137·2) months. Recurrences of hyperprolactinaemia were observed in 3 of 11 (27%) postwithdrawal patients at a median time of 3·0 (range; 2·9-11·2) months, indicating that a high percentage (73%) maintained remission for at least 12 months after cabergoline cessation. Factors significantly associated with remission were analysed in 21 patients receiving long-term cabergoline administration. On multivariate analysis, the absence of cavernous sinus invasion on pretreatment MRI (≥3/4 tumour encasement of the intracavernous internal carotid artery) (HR; 21·94, 95% CI; 2·06-1071·0, P = 0·006), initial PRL <132·7 ng/ml (HR; 8·28, 95% CI; 1·24-199·6, P = 0·03) and nadir PRL <1·9 ng/ml during cabergoline therapy (HR; 5·14, 95% CI; 1·10-39·02, P = 0·04) showed statistically significant correlations with remission after withdrawal. CONCLUSIONS: Cabergoline therapy can achieve a high percentage (73% in this series) of remission maintenance for at least 12 months after cessation of a 5-year course of therapy, even in patients with macroprolactinomas. The absence of cavernous sinus invasion, serum PRL level lower than 132·7 ng/ml before cabergoline therapy or nadir serum PRL below 1·9 ng/ml were related to more frequent remission after withdrawal of cabergoline in patients receiving this medication for 5 years.

Assessment of PD-1 positive cells on initial and secondary resected tumor specimens of newly diagnosed glioblastoma and its implications on patient outcome.

Glioblastoma (GBM) is the most common type of malignant brain tumor and has a very poor prognosis. Most patients relapse within 12 months despite aggressive treatment and patient outcome after recurrent is extremely worse. This study was designed to clarify the change of the molecular expression, including programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1), on the initial and secondary resected tumor specimens and to address the influence of these expressions for patient outcome after second surgery of glioblastoma. We investigated 16 patients, ranging in age from 14 to 65 years, with histologically verified WHO grade IV GBM, whose original tumor was resected between 2008 and 2014, and treated with fractionated radiotherapy and temozolomide. Four patients who were treated with immunotherapy using autologous formalin-fixed tumor vaccine were enrolled. All of the patients underwent secondary resection after tumor recurrence within 24 months. We carried out an immunohistochemical examination of the initial and secondary resected tumors from patients using a panel of immune system molecular markers, and assessed whether marker expression correlated with clinical outcomes. CD3, CD8 and PD-1 on tumor-infiltrating lymphocytes was significantly increased in secondary resected specimens compared with initially resected specimens (p ≤ 0.05). All patients expressed PD-L1 on tumor cells in initial and secondary resection specimens. Patients were divided into high or low expression group by median IHC score of PD-1 on initial or secondary resected specimens. No significant differences in patient outcomes were observed between high and low PD-1 or PD-L1 groups of initially resected specimens. In high expression group of secondary resected specimens, most patients score had increased which compared with initial resected tumor specimens. The PD-1 high expression score group of secondary resected specimens was associated with long progression-free survival and short survival after recurrence. PD-L1 expression was detected in almost all initial and secondary specimens. Patients with high PD-1 expression of secondary specimen had bad prognosis after secondary resection. PD-1/PD-L1 pathway may be associated with patient outcome after second surgery of glioblastoma.

[Combination Therapy with Radiation, Temozolomide, and Bevacizumab after Partial Tumor Removal in Glioblastoma Patients with Low Performance Status].

INTRODUCTION: It is unclear whether or not bevacizumab(Bev)has a curative ability in newly diagnosed glioblastoma(GBM) patients with low Karnofsky performance status(KPS). MATERIALS AND METHODS: Four of 14 patients with newly diagnosed GBM received combination therapy with extended local radiation, temozolomide(TMZ), and Bev after partialremovalor biopsy of the tumor. RESULTS: The average patient age was 77.2 years(range 67-85)and the male-to-female ratio was 1:3. In all cases, magnetic resonance imaging showed that combination therapy decreased tumor volume and peritumoral edema volume. The therapy was successfully administered to 3 patients without decreasing their KPS. However, 1 patient with seeding lesions dropped out of therapy because of deteriorating consciousness and decreasing KPS. DISCUSSION: Subgroup analysis in a randomized control study(AVAglio)showed that patients with a PS score of 1-2(corresponding to a KPS score of 60-80)tended to have prolonged survival after Bev treatment compared with those with a PS score of 0(corresponding to a KPS score of 90-100). In the present study, radiochemotherapy with Bev decreased lesion and edema volumes in all patients, and led to maintained or improved KPS in 3 patients. These results suggest that the treatment is potentially effective for patients with newly diagnosed GBM and lower KPS.

An Alkyloxyphenyl Group as a Sterically Hindered Substituent on a Triphenylamine Donor Dye for Effective Recombination Inhibition in Dye-Sensitized Solar Cells.

Recombination reactions in dye-sensitized solar cells (DSSCs) may substantially decrease the open-circuit voltage (Voc) with cobalt complex redox electrolyte. Managing steric hindrance in the dye structure is necessary to inhibit recombination reactions and thereby increase the Voc and achieve high power-conversion efficiency (PCE). New dyes with large-sized donors based on triphenylamine and modified with 4-(hexyloxy)phenyl groups were developed to identify an effective inhibitor for the recombination reaction in DSSCs with a cobalt complex redox electrolyte. The 4-(hexyloxy)phenyl tetra-adducts dye MK-123 effectively inhibited the recombination reaction, and the DSSC fabricated using this dye exhibited the highest Voc (greater than 900 mV) among the cells with the investigated dyes. However, the short-circuit current (Jsc) of the MK-123 cell was lower than that of the cell with the simple triphenylamine donor dye, MK-89. In contrast, the cell with bis-adducts dye MK-136 also exhibited an increase in its Voc without a decrease in its Jsc. Among the investigated dyes, MK-136 exhibited the highest PCE of 8.9%. The effects of the steric hindrance of the 4-(hexyloxy)phenyl substituent are discussed.

Proton beam therapy with concurrent chemotherapy for glioblastoma multiforme: comparison of nimustine hydrochloride and temozolomide.

To evaluate the safety and efficacy of postoperative proton beam therapy (PBT) combined with nimustine hydrochloride (ACNU) or temozolomide (TMZ) for glioblastoma multiforme (GBM). The subjects were 46 patients with GBM who were treated with high dose (96.6 GyE) PBT. There were 24 males and 22 females, and the median age was 58 years old (range 24-76). The Karnofsky performance status was 60, 70, 80, 90 and 100 in 5, 10, 12, 11 and 8 patients, respectively. Total resection, partial resection, and biopsy were performed for 31, 14 and 1 patients, respectively. Photon beams were delivered to high intensity areas on T2-weighted magnetic resonance imaging (MRI) in the morning (50.4 Gy in 28 fractions). More than 6 h later, PBT was delivered to the enhanced area plus a 10 mm margin in the first half of the protocol (23.1 GyE in 14 fractions) and to the enhanced volume in the second half (23.1 GyE in 14 fraction). Concurrent chemotherapy with ACNU during weeks 1 and 4 or daily TMZ was administered in 23 and 23 patients, respectively. The overall 1 and 2 year survival rates were 82.6 and 47.6 %, respectively. Median survival was 21.1 months (95 % CI 13.1-29.2), with no significant difference in survival between the ACNU and TMZ groups. The patient characteristics were similar in the two groups. Late radiation necrosis occurred in 11 patients (six ACNU, five TMZ), but was controlled by necrotomy and therapy including bevacizumab. PBT concurrent with ACNU or TMZ was tolerable and beneficial for carefully selected patients with GBM.

[Endoscopic Endonasal Transethmoidal Biopsy for IgG4-Related Intraorbital Pseudotumor:A Case Report].

BACKGROUND: We experienced a case of intraorbital pseudotumor associated with IgG4-related disease, for which we successfully performed an endoscopic endonasal transethmoidal biopsy for the intraorbital pseudotumor as well as endoscopic sinus surgery for a refractory pansinusitis at the same time. CASE REPORT: A 59-year-old man was referred to our hospital because of an intraorbital mass lesion. MRI showed 2 mass lesions:a large intraconal lesion encasing the left optic nerve on the orbital apex, and a small extraconal lesion medial to the left medial rectus muscle extending into the anterior ethmoid canal. In addition, CT showed severe pansinusitis. A blood test showed a marked elevation of IgG4. IgG4-related pseudotumor was suspected, but IgG4-related MALT lymphoma was an alternative diagnosis, and a biopsy of the mass lesion was required. We successfully performed both, an endoscopic endonasal transethmoidal biopsy for the mass lesion and endoscopic sinus surgery for the refractory pansinusitis at the same time. The pathological diagnosis was an IgG4-related pseudotumor. CONCLUSION: Endoscopic endonasal transethmoidal biopsy is an effective and minimally invasive method for making a definitive diagnosis of IgG4-related intraorbital pseudotumor. Using this method, refractory pansinusitis frequently associated with this disease can be treated. For successful treatment, interdisciplinary decision making and collaborative team surgery are crucial.

A high-sensitive HMab-2 specifically detects IDH1-R132H, the most common IDH mutation in gliomas.

Isocitrate dehydrogenase 1 (IDH1) mutations have been detected in gliomas and other tumors. Although IDH1 catalyzes the oxidative carboxylation of isocitrate to α-ketoglutarate (α-KG) in cytosol, mutated IDH1 proteins possess the ability to change α-KG into the oncometabolite D-2-hydroxyglutarate (D-2HG). Several monoclonal antibodies (mAbs) specific for IDH1 mutations have been established, such as H09, IMab-1, and HMab-1 against IDH1-R132H, which is the most frequent IDH1 mutation in gliomas. In this study, we established a novel high-sensitive mAb HMab-2, which reacts with IDH1-R132H but not with wild type IDH1 in ELISA. HMab-2 reacted only with IDH1-R132H, not with wild type IDH1/2 and other IDH1/2 mutants in Western-blot analysis. Furthermore, HMab-2 recognized IDH1-R132H more sensitively compared with our previously established HMab-1. HMab-2 detected endogenous IDH1-R132H protein expressed in glioblastoma in immunohistochemical analysis. HMab-2 is expected to be useful for the diagnosis of IDH1-R132H-bearing tumors.

Genome-wide identification of endothelial cell-enriched genes in the mouse embryo.

The early blood vessels of the embryo and yolk sac in mammals develop by aggregation of de novo-forming angioblasts into a primitive vascular plexus, which then undergoes a complex remodeling process. Angiogenesis is also important for disease progression in the adult. However, the precise molecular mechanism of vascular development remains unclear. It is therefore of great interest to determine which genes are specifically expressed in developing endothelial cells (ECs). Here, we used Flk1-deficient mouse embryos, which lack ECs, to perform a genome-wide survey for genes related to vascular development. We identified 184 genes that are highly enriched in developing ECs. The human orthologs of most of these genes were also expressed in HUVECs, and small interfering RNA knockdown experiments on 22 human orthologs showed that 6 of these genes play a role in tube formation by HUVECs. In addition, we created Arhgef15 knockout and RhoJ knockout mice by a gene-targeting method and found that Arhgef15 and RhoJ were important for neonatal retinal vascularization. Thus, the genes identified in our survey show high expression in ECs; further analysis of these genes should facilitate our understanding of the molecular mechanisms of vascular development in the mouse.

IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells.

Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.

CXCL12 secreted from glioma stem cells regulates their proliferation.

Emerging evidence suggests that the chemokine CXCL12 and its receptor CXCR4, which are expressed by glioma stem cells (GSCs), play an important role in tumorigenesis. To provide evidence for establishing a new therapy targeting the CXCL12/CXCR4 pathway, we investigated whether CXCL12 secreted from GSCs contributed to their proliferation and promoted angiogenesis in murine GSCs. Angiogenetic functions and proliferation of GSCs with or without CXCL12 inhibitors were evaluated in an in vitro model using tube formation assays, RT-PCR, and proliferation, as well as in an in vivo syngenic model. In endothelial culture, the morphology and gene expression of GSCs changed from stem cell-like characteristics to endothelial cell-like features. CXCL12 expression increased in endothelial cell-like GSCs. CXCL12 blockage with siRNA or shRNA markedly inhibited cell proliferation in vitro. CXCL12 knockdown with shRNA also inhibited tumor growth in vivo. On the other hand, CXCL12/CXCR4 blockage affected neither tube formation in vitro nor angiogenesis in vivo. The CXCL12 secreted from GSCs (autocrine/paracrine CXCL12) regulates their proliferation, but probably not angiogenesis.

Recent Status of Phase I Clinical Trials for Brain Tumors: A Regulatory Science Study of Exploratory Efficacy Endpoints.

BACKGROUND: Appropriate exploratory efficacy data from Phase I trials are vital for subsequent phases. Owing to the uniqueness of brain tumors (BTs), use of different strategies to evaluate efficacy is warranted. We studied exploratory efficacy evaluation in Phase I trials involving BTs. METHODS: Using Clarivate's Cortellis™, 42 Phase I trials of BT interventions conducted from 2020 to 2022 were analyzed for efficacy endpoints, which were set as primary endpoints (PEs) or secondary endpoints (SEs). Additionally, these metrics were compared in two subgroups: trials including only BTs (Group-A) and those including BTs among mixed solid tumors (Group-B). RESULTS: Selected studies included a median of 1.5 PEs (range, 1-6) and 5 SEs (range, 0-19). Efficacy endpoints were included as PEs and SEs in 2 (5%) and 31 (78%) trials, respectively. Among the latter 31 trials that included 94 efficacy endpoints, 24, 22, 20, 9, and 8 reflected overall response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and disease control rate (DCR), respectively. ORR for BT was determined using various methods; however, the Response Evaluation Criteria in Solid Tumors (RECIST) was used less frequently in Group-A than in Group-B (p = 0.0039). CONCLUSIONS: Recent Phase I trials included efficacy endpoints as SEs, with ORR, PFS, or OS included in ~ 50% trials and DOR or DCR in ~ 25%. No established criteria exist for imaging evaluation of BTs. Phase I trials involving mixed solid tumor cohorts revealed challenges in designing methods to assess the exploratory efficacy of BTs.

Establishment of novel monoclonal antibodies KMab-1 and MMab-1 specific for IDH2 mutations.

Isocitrate dehydrogenase 1/2 (IDH1/2) mutations have been detected in gliomas, cartilaginous tumors, and leukemias. IDH1/2 mutations are early and frequent genetic alterations, are specific to a single codon in the conserved and functionally important Arginine 132 (R132) in IDH1 and Arginine 172 (R172) in IDH2. We previously established several monoclonal antibodies (mAbs), which are specific for IDH1 mutations: clones IMab-1 or HMab-1 against IDH1-R132H or clone SMab-1 against IDH1-R132S. However, specific mAbs against IDH2 mutations have not been reported. To establish IDH2-mutation-specific mAbs, we immunized mice or rats with each mutation-containing IDH2 peptides including IDH2-R172K and IDH2-R172M. After cell fusion, IDH2 mutation-specific mAbs were screened in Enzyme-Linked Immunosorbent Assay (ELISA). Established mAbs KMab-1 and MMab-1 reacted with the IDH2-R172K and IDH2-R172M peptides, respectively, but not with IDH2-wild type (WT) in ELISA. Western-blot analysis also showed that KMab-1 and MMab-1 reacted with the IDH2-R172K and IDH2-R172M recombinant proteins, respectively, not with IDH2-WT or other IDH2 mutants, indicating that KMab-1 and MMab-1 are IDH2-mutation-specific. Furthermore, MMab-1 specifically stained the IDH2-R172M-expressing cells in immunocytochemistry, but did not stain IDH2-WT and other IDH2-mutation-containing cells. In immunohistochemical analysis, MMab-1 specifically stained IDH2-R172M-expressing glioma. This is the first report to establish anti-IDH2-mutation-specific mAbs, which could be useful in diagnosis of mutation-bearing tumors.

Decrease in the apparent diffusion coefficient in peritumoral edema for the assessment of recurrent glioblastoma treated by bevacizumab.

PURPOSES: Anti-edema effect of bevacizumab was evaluated using the apparent diffusion coefficient (ADC) of peritumoral edema associated with regional cerebral blood flow (rCBV) of the tumor. MATERIALS AND METHODS: Nine patients with recurrent glioblastoma were treated using bevacizumab for 4 ∼ 36 months (average 12 months). MRI was performed every 2 months. For each MRI, ADC value, Gd-enhanced area on T1 imaging, area of peritumoral edema on T2 imaging, and rCBV on perfusion imaging were measured. ADC and rCBV values were determined by the use of regions of interest positioned in areas of high signal intensity, as seen on T2-weighted images and ADC maps. RESULTS: After 2 months of bevacizumab treatment, ADC values and rCBV decreased 49 and 32 % respectively, associated with marked diminishment of the Gd-enhanced area compared with pretreatment. After 6 months, in 5 of the 9 cases, the Gd-enhanced area appeared again with no change in the ADC value and rCBV. In the other four cases, the Gd-enhanced area as well as the ADC value and rCBV returned to the initial status. CONCLUSION: The anti-edema effect of bevacizumab for treatment of recurrent glioblastoma that was demonstrated by decreased ADC values and rCBV was dramatic and -prolonged at 6 months even with tumor progression.

Risk Factors for Postoperative Cerebrospinal Fluid Leak after Graded Multilayer Cranial Base Repair with Suturing via the Endoscopic Endonasal Approach.

This study analyzed risk factors for postoperative cerebrospinal fluid (CSF) leak after graded multilayer cranial base repair method with dural suturing. We performed surgery via the endoscopic endonasal approach (EEA) from 2012.6 to 2018.4, and those consecutive clinical data were prospectively accumulated and retrospectively analyzed. We tailored the repair method according to the intraoperative CSF leak grade. Among 388 surgeries via the EEA, there were 10 (2.6%) cases of postoperative CSF leak after graded repair with suturing. Postoperative CSF leak occurred in two of the 150 cases without intraoperative CSF leak (grade 0), one of the 104 cases with small (grade 1) intraoperative CSF leak, two of the 60 cases with moderate (grade 2) leak, and five of the 74 cases with large (grade 3) leak. Univariate analysis indicated that chordoma (P = 0.023), estimated tumor volume ≥ 7400 mm3 (P = 0.003), and maximum tumor diameter ≥ 32.5 mm (P = 0.001) were significant risk factors for postoperative CSF leak. Additionally, among cases with intraoperative grade 3 CSF leak, chordoma (P = 0.021), estimated tumor volume ≥ 23000 mm3 (P = 0.003), and maximum tumor diameter ≥ 45.5 mm (P = 0.001) were significant risk factors for postoperative CSF leak. Maximum tumor diameter, estimated tumor volume, and chordoma tumor pathology are related to a higher risk of postoperative CSF leak.